Genomic Biomarker-Selected Therapy for Prostate Cancer

(GUNS Trial)

Recruiting at 8 trial locations

Overseen By Tiiu Sildva, PhD

Age: 18+

Sex: Male

Trial Phase: Phase 2

Sponsor: University of British Columbia

Must be taking: LHRHa, Apalutamide

Must not be taking: Androgens, Estrogens

Disqualifiers: T4 prostate cancer, Hypogonadism, HIV, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 7

315 Participants Needed

Trial Summary

What is the purpose of this trial?

The objective of this study is to see if providing an appropriate therapy based on the genomic testing of prostate tumour tissue will result in an improved clinical response. Each participant will be treated with 8 weeks of a luteinizing hormone-releasing hormone agonist (LHRHa) plus apalutamide (APA) while genome sequence characterization is being done. Participants with biopsy specimens deemed unevaluable for genomic testing will remain on LHRHa plus APA for an additional 16 weeks. Participants with evaluable tissue will be assigned to one of the open-label sub-studies on the basis of genomic profiling results. Within each group, they will be randomized to a specific treatment arm either LHRHa plus APA alone or adding abiraterone acetate and prednisone, docetaxel or niraparib. The study will evaluate the response rate and outcomes after radical prostatectomy in each arm of the trial.

Do I need to stop my current medications for this trial?

The trial does not specify if you need to stop taking your current medications. However, you cannot have received more than 30 days of certain prostate cancer treatments before joining the trial.

What data supports the effectiveness of the drug combination used in the clinical trial for prostate cancer?

Research shows that GnRH antagonists like degarelix can effectively reduce tumor growth and testosterone levels in prostate cancer, similar to surgical castration, which may enhance the effectiveness of other drugs like abiraterone in the treatment combination. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

The safety of treatments like degarelix and apalutamide has been studied in prostate cancer patients. Degarelix avoids 'testosterone flare' and has shown some advantages over other hormone therapies, while apalutamide has been evaluated for safety in clinical trials for prostate cancer. ^{1 2 4 6 7}

What makes the drug Apalutamide with LHRH agonist unique for prostate cancer treatment?

This treatment is unique because Apalutamide, when used with LHRH agonists, helps prevent the 'testosterone flare' that can occur with other hormone therapies, and it has been shown to improve survival in patients with certain types of prostate cancer. ^{1 2 3 6 8}

Research Team

Martin E Gleave, MD

Principal Investigator

University of British Columbia

Eligibility Criteria

Men over 18 with high-risk localized prostate cancer, no prior treatments for it, and willing to undergo genetic testing. They must have a life expectancy of at least 3 years and be in good health otherwise. Men with severe diseases, allergies to study drugs, or who can't take oral meds are excluded.

Inclusion Criteria

I have less than 3 metastases visible by PSMA imaging and am a candidate for radical prostatectomy.

My prostate cancer is considered high-risk.

Participant consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each participant must sign a consent form prior to enrolment in the trial to document their willingness to participate

Exclusion Criteria

M1 by conventional imaging (CT, bone scan)

My prostate cancer is advanced (Stage T4) as confirmed by tests.

You have had an allergic reaction to any of the study drugs or any of the substances used to make them.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction

Participants receive LHRHa plus apalutamide while genomic sequencing is performed

8 weeks

2 visits (in-person)

Sub-protocol Treatment

Participants are assigned to a treatment arm based on genomic profiling results

16 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 years

Annual visits (in-person)

Treatment Details

Interventions

• Abiraterone Acetate 250mg
• Apalutamide
• Docetaxel
• Luteinizing hormone-releasing hormone agonist (LHRHa)
• Niraparib 100mg Oral Capsule
• Prednisone 5mg Tab

Trial Overview The trial tests if targeted therapy based on genomic profiling improves response in men with prostate cancer. After initial treatment with hormone therapy plus apalutamide, participants may receive additional drugs like abiraterone acetate and prednisone, docetaxel or niraparib depending on their tumor's genetics.

Participant Groups

Group I: Group 1b Active Control 3 Interventions

LHRHa plus apalutamide plus abiraterone acetate plus prednisone.

Group II: Group 1a Active Control 1 Intervention

LHRHa plus apalutamide.

Group III: Group 2a Active Control 2 Interventions

LHRHa plus abiraterone acetate plus prednisone.

Group IV: Group 2b Active Control 3 Interventions

LHRHa plus abiraterone acetate plus prednisone plus docetaxel.

Group V: Group 3 Active Control 3 Interventions

LHRHa plus abiraterone acetate plus prednisone plus niraparib

Group VI: Group 4 Active Control 2 Interventions

LHRHa plus apalutamide plus atezolizumab

Apalutamide is already approved in United States, European Union for the following indications:

Approved in United States as Erleada for:

• Non-metastatic castration-resistant prostate cancer (nmCRPC)
• Metastatic castration-sensitive prostate cancer (mCSPC)

Approved in European Union as Erleada for:

• Non-metastatic castration-resistant prostate cancer (nmCRPC)
• Metastatic castration-sensitive prostate cancer (mCSPC)

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

Janssen Inc.

Industry Sponsor

Trials

24

Recruited

8,100+

University Health Network, Toronto

Collaborator

Trials

1,555

Recruited

526,000+

Findings from Research

Apalutamide effectively blocks androgen receptor signaling in metastatic hormone-sensitive prostate cancer, leading to a rapid decrease in PSA levels and increased testosterone during monotherapy, indicating its efficacy in treatment.

Administering apalutamide 1 hour before GnRH agonists not only simplifies the treatment process but also effectively prevents testosterone flare-up, achieving castration levels of testosterone by day 28 without worsening side effects like dysuria or bone pain.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absence of PSA Flare With Apalutamide Administered 1 Hour in Advance With GnRH Agonists: Case Report. Hu, Z., Liu, Z., Chen, Z., et al.[2022]

Degarelix, a GnRH receptor antagonist, significantly reduces prostate cancer cell viability compared to controls, while leuprolide, a GnRH agonist, can stimulate cell growth in the same cancer cell lines.

In animal studies, degarelix effectively lowers testosterone levels and tumor size compared to leuprolide, suggesting it may offer a more effective treatment option for managing prostate cancer without the 'testosterone flare' associated with LHRH agonists.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and AR-V7 Expression. Cucchiara, V., Yang, JC., Liu, C., et al.[2020]

GnRH antagonists provide faster suppression of hormones like luteinising hormone and testosterone compared to GnRH agonists, leading to improved disease control in advanced prostate cancer.

Patients receiving GnRH antagonists have a significantly lower risk of cardiac events within one year of treatment initiation, making them a safer option for men with pre-existing cardiovascular disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of gonadotrophin-releasing hormone antagonists in the treatment of patients with advanced hormone-dependent prostate cancer in the UK. Rosario, DJ., Davey, P., Green, J., et al.[2022]

In a study of 68 patients with metastatic prostate cancer, both leuprolide and triptorelin effectively reduced plasma testosterone levels, with leuprolide showing a faster decrease at 1 month.

While both treatments were effective in lowering testosterone, there were no significant differences in clinical efficacy or overall safety between the two LHRH analogues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Tolerance and clinical and biological responses during the first 6 months of treatment with 1-month sustained release LHRH agonists leuprolerin and triptolerin in patients with metastatic prostate cancer]. Abbou, CC., Lucas, C., Leblanc, V.[2018]

In a study of 242 prostate cancer patients, abarelix depot was found to prevent testosterone surges during the first week of treatment, unlike LH-RH agonists, which caused an 82% surge rate.

Abarelix depot achieved medical castration in 75% of patients within the first week, demonstrating faster efficacy and better tolerability compared to LH-RH agonists, which had no such rapid effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. Tomera, K., Gleason, D., Gittelman, M., et al.[2017]

In a study involving 39 patients with localized prostate cancer, neoadjuvant treatment with degarelix alone resulted in significantly higher levels of intratumoral dihydrotestosterone (DHT) compared to combinations of degarelix with bicalutamide or LHRH agonist with bicalutamide, suggesting a unique mechanism of action for degarelix.

Patients receiving degarelix had lower serum follicle-stimulating hormone (FSH) levels after 12 weeks compared to those on LHRH agonist, indicating potential advantages in hormonal regulation during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy. Sayyid, RK., Evans, A., Hersey, K., et al.[2017]

This clinical trial aims to evaluate the efficacy and safety of apalutamide in 110 patients with metastatic castration-resistant prostate cancer, focusing on the primary outcome of prostate-specific antigen (PSA) response rate, defined as a ≥50% decline from baseline at 12 weeks.

The study will also assess various secondary outcomes, including time to PSA progression and overall survival, while monitoring for any grade 3 or 4 adverse events, ensuring a comprehensive evaluation of both effectiveness and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of apalutamide in patients with metastatic castration-resistant prostate cancer (GENESIS): protocol for a multicentre, open-label, single-arm clinical trial. Miyake, H., Kakei, Y., Nakano, Y., et al.[2023]

In the SPARTAN study involving 1207 patients with nonmetastatic castration-resistant prostate cancer, apalutamide significantly improved health-related quality of life (HRQoL) compared to placebo, with patients maintaining better scores over time.

Patients receiving apalutamide experienced minimal side effects and reported no worsening of fatigue, while those on placebo showed a decline in quality of life after about one year, highlighting the efficacy and tolerability of apalutamide in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy. Oudard, S., Hadaschik, B., Saad, F., et al.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Absence of PSA Flare With Apalutamide Administered 1 Hour in Advance With GnRH Agonists: Case Report. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

GnRH Antagonists Have Direct Inhibitory Effects On Castration-Resistant Prostate Cancer Via Intracrine Androgen and AR-V7 Expression. [2020]

3. Germany pubmed.ncbi.nlm.nih.gov

The role of gonadotrophin-releasing hormone antagonists in the treatment of patients with advanced hormone-dependent prostate cancer in the UK. [2022]

4. France pubmed.ncbi.nlm.nih.gov

[Tolerance and clinical and biological responses during the first 6 months of treatment with 1-month sustained release LHRH agonists leuprolerin and triptolerin in patients with metastatic prostate cancer]. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

The gonadotropin-releasing hormone antagonist abarelix depot versus luteinizing hormone releasing hormone agonists leuprolide or goserelin: initial results of endocrinological and biochemical efficacies in patients with prostate cancer. [2017]

6. United States pubmed.ncbi.nlm.nih.gov

A Phase II, Randomized, Open-Label Study of Neoadjuvant Degarelix versus LHRH Agonist in Prostate Cancer Patients Prior to Radical Prostatectomy. [2017]

7. England pubmed.ncbi.nlm.nih.gov

Efficacy and safety of apalutamide in patients with metastatic castration-resistant prostate cancer (GENESIS): protocol for a multicentre, open-label, single-arm clinical trial. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy. [2022]